Field of Invention
The invention relates to the field of targeted cancer therapy. In particular, the invention relates to the identification of therapeutic target genes in individual cancer patients which do not represent oncogenes or tumor suppressor genes but have become putative therapeutic targets due to constraints of the cancer genome architecture on individual somatic cancer evolution.
Background Art
Cancer as a devastating but variable disease has always been subject of various theories, many of them sharing an explicit or implicit holistic or systems approach. Today, the scientific community has widely accepted the concept that cancer is caused by changes within the cellular genome [Knudson 1971, Fearon and Vogelstein, 1990]. This view may be regarded as a specification of Boveri's idea that somatic mutations are the basis of cancer [Boveri 1914].
Tumorigenesis and tumor progression can be considered an evolutionary process in which mutant and more tumorigenic subpopulations are sequentially selected and derived from less tumorigenic or benign progenitor cells [Foulds 1954, Nowell 1976, Gatenby and Vincent 2003]. The two main driving forces of tumorigenesis are on one hand a positive growth selection which may be mediated by external influences as well as by mutations in genes responsible for cell growth and apoptosis regulation and on the other hand an enhanced mutation rate leading to genetic instability.
Several human diseases are associated with an enhanced mutation rate and a predisposition to cancer. The mechanisms leading to genomic instability are multiple as multiple different systems exist which maintain genome integrity and which target different forms of DNA damage. The best known examples of genomic instability are post replicative mismatch repair (MMR) deficiency leading to mutations of short repetitive sequences such as microsatellite DNA (microsatellite instability=MIN) and chromosomal instability (=CIN) which induces rearrangement, loss, amplification or duplication of chromosomes or chromosome fragments resulting in aneuploidy. Besides, various other mechanisms exist such as defective nucleotide excision repair (NER), defective base excision repair (BER) and defective cell cycle checkpoint controls. It has been shown that human tumors with deficiency of MMR display different mutation patterns at target genes involved in carcinogenesis than tumors with chromosomal instability (CIN) [Zhou et al. 2002]. DNA-repair systems such as MMR and NER are constituted of multiple proteins and defects of different factors within a DNA repair system may result in differing mutation frequencies, mutation spectra and mutation hotspots within coding and non-coding DNA. This has been demonstrated in bacterial, yeast and animal models [Schaaper and Dunn et al. 1987, Habraken et al. 1996, Marti et al. 2003, Harfe and Jinks-Robertson 2000, Denver et al. 2006, Denver et al. 2005, Yao et al. 1999, Kuraguchi et al. 2001, Andrew et al. 2000]. Defects of mechanisms ensuring chromosomal stability such as lack of repair of double strand breaks, telomere loss, centrosome amplification, homologous recombination deficiency or suppression of hyperrecombination do also induce specific types of mutations [Lobachev et al. 2002, Traverso et al. 2003, Sabatier of al. 2005; Michor 2005, Deans et al. 2003; Saunders 2005, Bailey and Murnane 2006].
Most clinically distinguishable malignant tumors are characterized by specific mutations, specific patterns of chromosomal rearrangements and a predominant mechanism of genetic instability but it remains unsolved whether modifications of cancer genomes can be explained solely by mutations and positive or negative selection through the cancer microenvironment
It has been suggested that the internal dynamics of genomic modifications as opposed to the external evolutionary forces have a significant and complex impact on Darwinian species evolution [Conrad 1990, Shapiro 1999, Dover 2000, Poole et al. 2003, Brookfield 2009]. A similar situation can be expected for somatic cancer evolution as the key mechanisms encountered in species evolution such as duplications, rearrangements or deletions of genes [Demuth et a 2006] also constitute prevalent mutation mechanisms in cancers with chromosomal instability.